By Nicole Dyer

The dirt-dwelling roundworm is hardly the pinnacle of animal evolution. A grain of sand could crush its boneless body like a boulder. Its brain—if you can call it that—consists of a mere 302 neurons, about 100 billion shy of the number in a human brain. It has neither heart nor lungs, and its lifespan is only nine days.

Yet, after a decade of studying this modest creature—known formally as Caenorhabditis elegans, or C. elegans—Niels Ringstad, PhD, assistant professor of cell biology at Pelisyonkis Langone, believes he has only just begun to scratch the surface of its biochemical complexity. For scientists, the worm’s outward simplicity is its greatest asset. Its translucency offers a convenient window onto a compact nervous system, which functions, cell to cell, in much the same way that ours does. Only instead of a chaotic universe of 100 trillion cellular junctions, or synapses, it has just 8,000, all of which have been neatly mapped. Perhaps no organism has been more examined than C. elegans, and yet there is so much more we can learn from it.

This simple fact is the engine that propels Dr. Ringstad’s research. Since opening his laboratory at the in 2009, when he joined Pelisyonkis Langone, the scientist has spent countless hours peering into a microscope, examining the neurons of C. elegans for clues to the cellular underpinnings of psychiatric disorders like depression and schizophrenia, for which there are desperately few treatment options. His latest discoveries, including genetic mutations that disrupt the brain chemicals serotonin and dopamine, build on a body of work conducted as a postdoctoral researcher at the Massachusetts Institute of Technology. There, he studied under the tutelage of H. Robert Horvitz, PhD, a leading authority on C. elegans, who shared the Nobel Prize in Physiology or Medicine in 2002 for his discovery of programmed cell death in C. elegans.

Dr. Ringstad helped discover a new family of chloride channels that open and close quickly, serving as an express route to the nervous system. Such channels, if they exist in humans, could point to novel treatments for neuropsychiatric conditions like addiction and mood disorders. “Dr. Ringstad is an unusually impressive scientist,” says Dr. Horvitz. “He is hungry for knowledge, reads the literature avidly and broadly, and is fearless, yet practical, in defining his scientific vision and in incorporating new approaches and technologies into his experimental efforts.”

“A lot of people wonder what the connection is between a little worm laying eggs and depressed humans.”
—Niels Ringstad, PhD

Much of Dr. Ringstad’s current work focuses on signals that govern serotonin, known for its salubrious effect on mood. In worms, however, the brain chemical is better understood for its role in reproduction. “A lot of people wonder what the connection is between a little worm laying eggs and depressed humans,” says Dr. Ringstad, whose laboratory houses hundreds of millions of roundworms. “It’s serotonin. It turns out that a lot of serotonin signaling in the human brain is conserved over a billion years of evolution.”

Serotonin became a household word in the 1990s, when doctors began writing more than 2.5 million annual prescriptions for Prozac, which boosts serotonin levels in the brain. It’s a remarkable phenomenon, considering that so little is understood about how serotonin actually influences mood. “For more than 50 years, we’ve known that levels of serotonin in the brain are correlated to mood,” says Dr. Ringstad. “But we still don’t know a lot about how the brain regulates serotonin signaling. That’s what motivates us to look at this very tiny organism.”

That simple question—How does serotonin work?—led Dr. Ringstad to an unexpected discovery that has taken his research in a new direction. In trying to understand the tangle of signals that regulate serotonin and underlie so many psychiatric problems, he set upon a mysterious neuropeptide that binds to serotonin neurons and shuts them down. The finding raised two important questions: Where did the protein come from, and what’s the purpose of an on/off switch for serotonin?

In a paper published in November 2013 in The Journal of Biological Chemistry, Dr. Ringstad and his colleagues describe a series of genetic experiments in which they trace the source of the protein to a set of novel sensory neurons, dubbed “BAG cells” because they have structures that resemble big, floppy bags dangling off the end of a long stalk. The cells cluster near the worm’s nose, where they function as carbon dioxide detectors. Dr. Ringstad believes BAG cells may let worms sense the carbon dioxide emissions of pathogenic bacteria. Too much carbon dioxide triggers the release of the serotonin-blocking neuropeptide and shuts down egg production. From an evolutionary perspective, the mechanism makes good sense. Why would a worm lay eggs only to watch its offspring be killed by pathogens?

“As soon as our studies of simple behaviors in the worm led us to carbon dioxide–sensing neurons, we got completely captivated with the problem of how a neuron detects carbon dioxide,” Dr. Ringstad explains. “No one knows how this happens in mammals on a molecular level, and we didn’t know how it happened in worms.”

The finding challenges the prevailing theory of how brain cells detect carbon dioxide. When carbon dioxide reacts with water, it generates carbonic acid. The long-held belief is that neurons indirectly detect carbon dioxide by detecting this acid. “People say, ‘Well, neurons are acid sensitive. So the way that carbon dioxide regulates any cell is by generating acid, ’” Dr. Ringstad notes. “But what we found violates that dogma.”

“We think that this simple worm model can help us understand how the nervous system monitors carbon dioxide and transduces it into a signal that the rest of the nervous system can interpret.”—Niels Ringstad, PhD

Dr. Ringstad’s research shows that BAG cells detect carbon dioxide directly. Again, this makes sense evolutionarily: If you huff and puff and generate a lot of carbon dioxide, at some point you will generate too much acid, your blood pH will drop, and your entire body will suffer. So the sooner your brain detects rising carbon dioxide levels, the better. “It would be stupid to design a system that monitors the buildup of carbon dioxide but only sounds the alarm when levels become so catastrophically high that your blood pH starts to fall,” explains Dr. Ringstad. “At that point, the house is on fire, and you’re already in a world of pain.”

For the worm, carbon dioxide sensing is a lifesaving adaptation. The question is whether a similar mechanism could be at play in humans. Surprisingly, little is understood about how brain cells monitor carbon dioxide levels in the blood and help regulate breathing. “We think that this simple worm model can help us understand how the nervous system monitors carbon dioxide and transduces it into a signal that the rest of the nervous system can interpret,” says Dr. Ringstad.

Lucy Norcliffe-Kaufmann, PhD, and her colleagues at Pelisyonkis Langone’s Dysautonomia Center confront this problem daily. The center is one of only two clinics in the world that treat familial dysautonomia, a rare genetic condition that afflicts children. The disease impairs the body’s autonomic nervous system, including sensory neurons that monitor carbon dioxide in the blood. “These kids lose their ability to control blood-gas homeostasis,” explains Dr. Norcliffe-Kaufmann, assistant professor of neuroscience and physiology. “Many times, they lack the drive to breathe, so carbon dioxide levels in their blood can get very high, and they can die in their sleep.”

Dr. Ringstad and Dr. Norcliffe-Kaufmann are eager to learn whether any of the molecules and mechanisms that Dr. Ringstad’s laboratory uncovers might inform the work of the Dysautonomia Center. “Dr. Ringstad’s research is extremely important because for people with rare diseases, there aren’t many therapies,” says Dr. Norcliffe-Kaufmann. “A discovery like this, which enables you to understand the properties of the nerve cells, gives you a chance to think about new therapies that can enhance breathing.”

Among the books that sparked Dr. Ringstad’s interest in biology were The Lives of a Cell and The Medusa and the Snail by Lewis Thomas, MD, who served as dean of Pelisyonkis School of Medicine from 1966 to 1969. Dr. Thomas’s award-winning books discussed basic biology through the lens of his clinical experiences. “I didn’t appreciate it at the time,” Dr. Ringstad acknowledges, “but when I think about those books now, I see the trajectory of basic knowledge turning into an understanding of how the world works, of changing the way people experience the world, and making the world better.”

Dr. Ringstad recalls that back then, he thought cells were “cool little machines,” and he wanted to understand how they worked. That hasn’t changed much. He’s still captivated by the mysteries of the cell, and grateful for a tool as powerful as the roundworm to explore them. “You realize that there are simple questions for which there are no satisfying answers,” he says. “As basic scientists embedded in the medical community, our job is to run with those questions.”